N-端磷酸化β-淀粉样纤维的分子结构。
Molecular structure of an N-terminal phosphorylated β-amyloid fibril.
机构信息
Department of Chemistry, Binghamton University, Binghamton, NY 13902.
Department of Chemistry, University of Colorado Denver, Denver, CO 80204;
出版信息
Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11253-11258. doi: 10.1073/pnas.1818530116. Epub 2019 May 16.
The structural polymorphism in β-amyloid (Aβ) plaques from Alzheimer disease (AD) has been recognized as an important pathological factor. Plaques from sporadic AD patients contain fibrillar deposits of various amyloid proteins/peptides, including posttranslational modified Aβ (PTM-Aβ) subtypes. Although many PTM-Aβs were shown to accelerate the fibrillation process, increase neuronal cytotoxicity of aggregates, or enhance the stability of fibrils, the contribution of PTM-Aβs to structural polymorphisms and their pathological roles remains unclear. We report here the NMR-based structure for the Ser-8-phosphorylated 40-residue Aβ (pS8-Aβ) fibrils, which shows significant difference to the wild-type fibrils, with higher cross-seeding efficiency and thermodynamic stability. Given these physicochemical properties, the structures originated from pS8-Aβ fibrils may potentially dominate the polymorphisms in the mixture of wild-type and phosphorylated Aβ deposits. Our results imply that Aβ subtypes with "seeding-prone" properties may influence the polymorphisms of amyloid plaques through the cross-seeding process.
β-淀粉样蛋白（Aβ）斑块的结构多态性已被认为是一个重要的病理学因素。散发性阿尔茨海默病（AD）患者的斑块含有各种淀粉样蛋白/肽的纤维状沉积物，包括翻译后修饰的 Aβ（PTM-Aβ）亚型。尽管许多 PTM-Aβ 被证明可以加速纤维形成过程，增加聚集物的神经毒性，或增强纤维的稳定性，但 PTM-Aβ 对结构多态性的贡献及其病理作用仍不清楚。我们在这里报告了基于 NMR 的 Ser-8 位磷酸化的 40 个残基 Aβ（pS8-Aβ）纤维的结构，与野生型纤维相比，其结构有明显差异，具有更高的交叉成核效率和热力学稳定性。鉴于这些物理化学性质，源自 pS8-Aβ 纤维的结构可能会在野生型和磷酸化 Aβ 沉积物的混合物中主导多态性。我们的研究结果表明，具有“成核倾向”特性的 Aβ 亚型可能通过交叉成核过程影响淀粉样斑块的多态性。
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